Activity-dependent regulation of the dopamine phenotype in substantia nigra neurons

Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms of Parkinson's disease. The development of cell-replacement therapies for Parkinson's disease motor symptoms is hampered by poor acquisition and retention of the DA phenotype by endogenous and transplanted neurons. Factors which regulate the DA phenotype in the adult SNc are, therefore, keenly sought. Transcription of the rate-limiting enzyme in DA synthesis, tyrosine hydroxylase, and possibly other DA genes, is known to be regulated by changes in membrane potential and intracellular Ca²⁺. Furthermore, emerging evidence indicates DA gene transcription is sensitive to fast membrane potential changes and intracellular Ca²⁺ transients, that is, those associated with normal rates and patterns of neuronal activity. In other words, the DA phenotype is activity-dependent. In this review, we highlight the importance of spatiotemporal Ca²⁺ dynamics for regulating gene expression in cells, and the possible role of fast Ca²⁺ dynamics associated with normal rates and patterns of neuronal activity. We review evidence supporting activity- and Ca²⁺-dependent regulation of the DA phenotype in cells, including SNc neurons, as well as knowledge about the molecular pathways intervening between intracellular Ca²⁺ and TH gene expression. We describe the electrophysiology of SNc DA neurons, emphasizing features that may regulate DA gene expression. We conclude by bringing together this information in a model of how neuronal activity might regulate the DA phenotype in SNc neurons.